The free tetra acid, N-(phosphonoacetyl)-L-aspartic acid (sometimes referred to herein as PALA), is a known compound. The present invention relates to novel N-(phosphonoacetyl)-L-aspartic acid (PALA) compounds, especially disodium PALA, and to methods for preparation of N-(phosphonoacetyl)-L-aspartic acid compounds. A particular aspect of the present invention is concerned with the large-scale preparation of the known tetrasodium salt and the novel disodium salt of N-(phosphonoacetyl)-L-aspartic acid.
The known tetra acid compound, N-(phosphonoacetyl)-L-aspartic acid (PALA), was first prepared by Stark et al., J. Biol. Chem., 246, 6599 (1971). The tetrasodium salt of PALA is a known antitumor agent, as reported in the literature, particularly Cancer Research, 36, 2720 (1976), incorporated herewith by reference. For example, the survival time of mice bearing intraperitoneal P388 leukemia was prolonged by up to 64% (when treated with PALA tetrasodium salt in a dose range of 188 to 750 mg./kg., i.p.). Lewis lung sarcoma was highly sensitive to PALA tetrasodium salt in mice at i.p. doses from 240 to 490 mg./kg. Mice bearing B16 melanoma survived 77 to 86% longer than did controls when treated with PALA tetrasodium salt (490 mg./kg., i.p.).
While the synthesis of the tetra acid PALA is straight-forward, the preparation of the tetrasodium salt, especially in kilogram quantities, has proven to be a major problem. The methods of the present invention are particularly well-suited for the production of such quantities.